Project Summary: Parkinson?s disease (PD) is characterized by a progressive loss of midbrain dopaminergic neurons in the substantia nigra pars compacta (SNpc), resulting in movement defects. A variety of dominant and recessive genetic mutations have recently been identified in families with a high prevalence of PD (fPD), accounting for ~15% of all PD cases. A defining pathological feature of both fPD and sporadic PD is the presence of intracellular protein aggregates termed Lewy bodies (LB), whose major component is the protein alpha-synuclein (?-syn). Interestingly, ?-syn has recently been hypothesized to exhibit certain ?prion-like? properties, such as the ability to spread through the brain and trigger ?-syn aggregation in interconnected brain regions. Moreover, local injection of ?-syn fibrils into the brains of wild type (WT) mice leads to aggregation of ?-syn within neurons of connected regions distant from the injection site. Together, these findings indicate that ?-syn can be taken up by neurons and transmitted to other neurons in interconnected brain areas, where it can trigger aggregation. Although considerable progress has been made in support of the progressive nature of ?-syn pathology, the mechanism controlling of ?-syn aggregation remains poorly understood. Recent studies have suggested that autophagic and endosomal pathways are involved. However, these general protein degradation pathways are ubiquitously expressed in all cells, targeting these pathways may cause severe side effects. Therefore, it is critical to identify dopamine neuron specific pathway that is critical for regulating ?-syn aggregation. One unique role of dopaminergic neurons is to synthesize and metabolize the neurotransmitter, dopamine. The metabolic product of dopamine, 3,4-dihydroxyphenylacetaldehyde (DOPAL), is highly reactive and promote cytotoxic polymerization of PD-related ?-syn. We hypothesize that enhancing aldehyde dehydrogenase 1a1 (ALDH1a1) ? the key enzyme involved in oxidation of DOPAL in dopamine neurons- would decrease ?-syn burden in vivo thereby attenuating neuronal and behavioral defects associated with synucleinopathy. We will examine 1) whether ALDH1a1 loss of function would enhance ?-syn aggregation in vivo; 2) whether inhibiting upstream enzyme monoamine oxidase (MAO) would decrease ?-syn aggregation and ?-syn fibril propagation; 3) whether overexpression or elevate ALDH1a1 function would be beneficial to protect dopamine neuron against ?-syn aggregation. Completion of this study will provide important validation of ALDH1a1 as a viable target for Parkinson?s disease therapy. Ultimately, the proposed experiments will be a major step towards the understanding of transmission and aggregation of ?-syn in Parkinson?s disease.